rs434102

Variant names:

• chr6-42698323-T-C
• rs434102
• NM_000322.5:c.1013A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-42698323-T-C
• chr6-42698323-T-A
• chr6-42698323-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000322.5(PRPH2):​c.1013A>G​(p.Asp338Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,613,846 control chromosomes in the GnomAD database, including 502,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D338D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.77 (45659 hom., cov: 31)
  • Exomes 𝑓: 0.79 (456515 hom.)
• Consequence: PRPH2 NM_000322.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.27
• Publications: 51 publications found

Genes affected

PRPH2 (HGNC:9942): (peripherin 2) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis. Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. [provided by RefSeq, Jul 2008]

PRPH2 Gene-Disease associations (from GenCC):

• hereditary macular dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• PRPH2-related retinopathy

  Inheritance: AD, SD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• Leber congenital amaurosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• retinitis pigmentosa 7

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• choroidal dystrophy, central areolar 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• fundus albipunctatus

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• vitelliform macular dystrophy 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• inherited retinal dystrophy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• adult-onset foveomacular vitelliform dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• central areolar choroidal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multifocal pattern dystrophy simulating fundus flavimaculatus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• patterned macular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis punctata albescens

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 126 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.10182 (below the threshold of 3.09). Trascript score misZ: 0.57529 (below the threshold of 3.09). GenCC associations: The gene is linked to inherited retinal dystrophy, fundus albipunctatus, retinitis pigmentosa 7, choroidal dystrophy, central areolar 2, adult-onset foveomacular vitelliform dystrophy, retinitis punctata albescens, hereditary macular dystrophy, central areolar choroidal dystrophy, Leber congenital amaurosis, vitelliform macular dystrophy 3, multifocal pattern dystrophy simulating fundus flavimaculatus, PRPH2-related retinopathy, cone-rod dystrophy, retinitis pigmentosa, patterned macular dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=8.6911155E-7).
• BP6: Variant 6-42698323-T-C is Benign according to our data. Variant chr6-42698323-T-C is described in ClinVar as Benign. ClinVar VariationId is 138906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000322.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH2	NM_000322.5	MANE Select	c.1013A>G	p.Asp338Gly	missense	Exon 3 of 3	NP_000313.2	P23942

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH2	ENST00000230381.7	TSL:1 MANE Select	c.1013A>G	p.Asp338Gly	missense	Exon 3 of 3	ENSP00000230381.5	P23942

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117622 AN: 151942 Hom.: 45623 Cov.: 31

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.932

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.776 AC: 194604 AN: 250756 AF XY: 0.776

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.698

Gnomad EAS exome AF: 0.862

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.789 AC: 1153927 AN: 1461786 Hom.: 456515 Cov.: 82 AF XY: 0.788 AC XY: 573068 AN XY: 727198

African (AFR) AF: 0.731 AC: 24465 AN: 33478

American (AMR) AF: 0.714 AC: 31944 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 18306 AN: 26136

East Asian (EAS) AF: 0.849 AC: 33697 AN: 39700

South Asian (SAS) AF: 0.740 AC: 63835 AN: 86256

European-Finnish (FIN) AF: 0.810 AC: 43231 AN: 53362

Middle Eastern (MID) AF: 0.768 AC: 4423 AN: 5762

European-Non Finnish (NFE) AF: 0.797 AC: 886624 AN: 1111976

Other (OTH) AF: 0.785 AC: 47402 AN: 60392

GnomAD4 genome AF: 0.774 AC: 117709 AN: 152060 Hom.: 45659 Cov.: 31 AF XY: 0.771 AC XY: 57335 AN XY: 74328

African (AFR) AF: 0.732 AC: 30353 AN: 41472

American (AMR) AF: 0.740 AC: 11311 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2479 AN: 3468

East Asian (EAS) AF: 0.858 AC: 4411 AN: 5142

South Asian (SAS) AF: 0.737 AC: 3557 AN: 4824

European-Finnish (FIN) AF: 0.800 AC: 8463 AN: 10574

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.801 AC: 54455 AN: 67978

Other (OTH) AF: 0.760 AC: 1604 AN: 2110

Alfa AF: 0.786 Hom.: 129675

Bravo AF: 0.768

TwinsUK AF: 0.777 AC: 2881

ALSPAC AF: 0.781 AC: 3009

ESP6500AA AF: 0.729 AC: 3213

ESP6500EA AF: 0.801 AC: 6890

ExAC AF: 0.778 AC: 94455

Asia WGS AF: 0.805 AC: 2801 AN: 3478

EpiCase AF: 0.792

EpiControl AF: 0.793

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Choroidal dystrophy, central areolar 2 (2)
-	-	2	Patterned macular dystrophy 1 (2)
-	-	2	Pigmentary retinal dystrophy (2)
-	-	1	Adult-onset foveomacular vitelliform dystrophy (1)
-	-	1	Cone-rod dystrophy (1)
-	-	1	not provided (1)
-	-	1	PRPH2-related disorder (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 7 (1)
-	-	1	Vitelliform macular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.92
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.53	D
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.028
Sift	Benign	0.25	T
Sift4G	Benign	0.41	T
Vest4		0.034
MPC		0.40
ClinPred		0.036	T
GERP RS		4.3
gMVP		0.42
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs434102; hg19: chr6-42666061; COSMIC: COSV57837122; COSMIC: COSV57837122;